Transdermal drug delivery devices have been in the literature for some time now and are seen to be of a number of different basic constructions. In their simplest forms there are the strict matrix monolith type devices and the membrane "sack" type devices. The simple strict monolith type has an active agent which is contained within a solid or semi-solid (capable of retaining its shape under light to moderately applied pressure) which is cast on or adhered to a backing layer impermeable to the passage of active agent. An adhesive may be only on or around the perimeter of or over the entire exposed surface (opposite that adjacent the backing layer) of the active agent containing layer. The simple "sack" type device has an active agent impermeable layer and a second layer (active agent permeable) affixed thereto such that the two layers define an active agent bulk reservoir for containing an active agent formulation. See especially U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,734,097; 3,742,951; 3,797,494; 3,948,254; 3,996,934; 4,284,444; 4,597,961; 4,666,441; 4,911,77; 4,915,950; 4,917,676; 4,460,372; 4,588,580; 4,597,961; 4,743,249; and 5,016,652; all of which are incorporated herein by reference.
In most all cases of the "sack" type transdermal drug delivery devices there are at least two components which must be sealed together, usually with the active agent or active agent formulation in place during the sealing operation. In many instances, the strict monolith type of device, the monolithic material is not adhesive in its own right or its adhesive properties are insufficient for the needs of commercial products. In these cases, the active agent containing material must be affixed to the backing layer by some alternative means, such as sealing, or adhering it via an adhesive, or overlayering it with another layer which overlayer is affixed to the backing (creating a hybrid between the "sack" type and strick monolith type devices).
In general the above mentioned devices have used adhesives, heat sealing techniques, and pressure sealing techniques, either alone or in various combinations when sealing of components has been needed for transdermal drug delivery devices. While these techniques have indeed been found acceptable for obtaining product which will meet regulatory approval and quality assurance requirements, there are significant drawbacks involved that, if overcome, would make the manufacture of such devices cheaper, more efficient, and the devices themselves more reliable.
For example, the range of adhesives that will assure suitable integrity of seal areas and which will not affect active agent formulation components or their delivery from the reservoir (whether a "sack" type reservoir or monolithic one) are few indeed. Adhesives useful for seal purposes must be impermeable to active agent formulation so as to retain the active agent formulation within the device and not create a reservoir to which the active agent will preferentially migrate during storage. Such migration, should it occur, would result in the delivery characteristics differing from those for which the product was designed or introduce an additional possibility for batch-to-batch variation in results. Neither of these situations is desired even if the differences in results introduced fall within tolerance levels for meeting regulatory and quality assurance performance characteristics.
Active agent impermeable adhesives cannot be used for sealing purposes in all instances either. Again, there is the problem of chemical interaction with the active agent formulation itself, thereby limiting the number of adhesives to be employed. Secondly, if the adhesive inadvertently gets onto the portion through which the active agent is intended to diffuse, the delivery characteristics of the device will vary from the intended performance characteristics.
Pressure sealing eliminates the problems inherent in the chemical sealing, since there is no concern for chemical interaction between the sealing means and the active agent formulation and there is no concern for inappropriate migration of active agent into the sealing means. However, pressure seals have there own problems associated with them. Simply put, in the process of applying the pressure seal, the active agent formulation can easily be displaced and the materials being sealed can shear. Furthermore, in an effort to avoid inadvertent displacement of the active agent formulation, the seal might be placed at a slightly further point from the center, resulting in a space in which the active agent formulation might migrate within the reservoir area. This could result in differences in performance of the device depending upon orientation of the device during storage and use. Typical pressures used to generate such pressure seals are in the range of 500 lbs to 1200 lbs.
The third sealing technique, heat sealing, also overcomes the problems associated with adhesive sealing, but introduces other problem areas. Again, these problems set forth below, do not prohibit the ability to meet the regulatory and quality assurance requirements associated with commercial products, but they introduce potential variables which preferrentially should be eliminated or at least reduced to increase the efficiency of manufacture and reduce the number of reject units.
In the heat sealing operation (or thermal-die process) a steel sealing die of specified geometry is heated to a temperature range significantly greater than the melting point of the thermoplastic materials being sealed together. High die temperatures are necessary to insure heat penetration through the thermoplastic materials and induce melt at the seal area. The problems inherent in this process are that excessive heat causes the laminate materials to shrink and distort, machine speed and temperature of the die are proportionally related so that high die temperatures are needed for high speed operation, the laminate material with the lowest melting point may flow out of the seal area before the seal can be formed so that the thermal bond is weakened, and the melted thermoplastic material remains in a hydraulic state for a brief period after the hot die is retracted during which tension forces may cause the laminate material to separate thereby weakening the seal. Finally, heat seal systems are limited to those components (including active agent formulation) which can withstand the temperatures applied without appreciable degredation.